OBJECTIVE: To
present a critical and updated review about sepsis, focusing especially on diagnosis
and treatment. SOURCE OF DATA: Literature review of Medline, including review articles,
clinical trials and original research. SUMMARY OF THE FINDINGS: The International Sepsis Definitions Conference
amplified the list of possible clinical and laboratory signs of sepsis, which
may allow for more efficacious suspicion and management. In terms of laboratory
evaluation, in addition to the research for infectious agents, many inflammatory
response markers, such as inflammatory cytokines and procalcitonin, have been
identified. However, they lack sensitivity and specificity for safe diagnosis.
In terms of treatment, early intervention to prevent hemodynamic disturbances
is still essential for a positive outcome, together with the appropriate use
of antimicrobials. The value of treatments to remove toxins and to increase
the innate immune response has not yet been established. The use of isolated
inflammatory response blockers, at any stage of sepsis, does not decrease mortality.
The use of corticosteroid makes a comeback with encouraging results, even in
patients without sepsis-related adrenal insufficiency. A large study on activated
protein C (drotrecogin-a) reports a 6% decrease in
mortality in a selected sample, suggesting the possibility of a better prognosis
for sepsis patients.
CONCLUSIONS: In comparison to the advances of the past few years, little
has been achieved in terms of decreasing sepsis-related mortality due to the
complexity of the pathogen-host relationships. The individual regulation of
host reactions did not have the expected effects. The benefits of some known
strategies were confirmed. Other types of treatment, such as corticosteroids
and activated protein C therapies, are emerging as promising alternatives. Research
indicates that the combination of immune modulator therapies is probably the
best choice to improve outcomes in sepsis.

"Our
arsenals for fighting off bacteria are so powerful,
and involve so many different defense mechanisms, that we are
more in danger from them than from the invaders.
We live in the midst of explosive devices; we are mined."

Lewis
Thomas, 1972

Introduction

Sepsis is a complex
syndrome caused by an uncontrolled systemic inflammatory response, of infectious
origin, characterized by multiple manifestations and which can result in dysfunction
or failure of one or more organs and even death.

During the last
decade innumerable advances were made in understanding the pathophysiology of
this syndrome, by means of multicenter studies, which resulted in the suggestion
of certain diagnostic markers and in the potential benefit of innumerable treatments
alternatives.1-3 In recent years researchers in recent years have
persistently pursued the achievement both of early diagnosis and of a change
or arrest of its clinical course. However, the poor clinical evolution and the
continued high mortality among sepsis patients do are not signs of an early
or successful outcome to the hunt for solutions to this condition.

Since the 1991
Consensus, new definitions and criteria for the diagnosis of sepsis, although
lacking specificity, particularly for pediatric patients,4 have enabled
researchers to speak the same language and compare the results of their experiments.
In 2001, the International Sepsis Definitions Conference, congregating a larger
number of researchers and experts from all over the world, opted not to modify
the existing definitions and to increase the list of signs and symptoms of sepsis
(Table 1), thus valuing the clinical experience of intensive
care professionals.5

The use of the
term sepsis is not restricted to a systemic inflammatory syndrome secondary
to bacterial infection, but to this syndrome resulting from any microorganism
and/or its products (toxins). The term sepsis is applicable only when the systemic
response is clinically relevant, which can manifest in a variety of situations
of increasing complexity: (a) severe sepsis, understood as sepsis associated
with organ failure, hypoperfusion (which includes, but is not limited to lactic
acidosis, oliguria or an acutely altered state of consciousness) and hypotension;
(b) septic shock, understood as sepsis associated with hypoperfusion alterations,
but with persistent hypotension even after suitable volumetric resuscitation,
and (c) multiple organ failure syndrome (MOFS), which may represent the final
stage of the severe systemic inflammatory reponse.5-7 However, the
limits which separate sepsis from severe sepsis and this from septic shock are
not easily detected in clinical at ICUs, or even from a conceptual point of
view.8,9 The last conference on sepsis proposed the development of
a system of stages for sepsis which would better classify the syndrome based
on pre-disposing factors and on pre-morbid conditions, in the nature of the
subjacent infection, in the characteristics of the response of the host and
the extension of resultant organ dysfunction (PIRO - Predisposition Infection
Response Organ Dysfunction).

Epidemiology

Sepsis is a heavy
burden on health services all over the world, both from economic and social
points of view. According to an epidemiological study of the USA, over the last
20 years, the incidence of sepsis increased from 82.7 to 240.4/100 thousand
inhabitants, as did the deaths related to it, although the general mortality
rate among patients with sepsis was reduced over the period.10 A
study by Watson et al., based on pediatric hospital discharge records in the
USA in 1995, revealed a prevalence of 0.56 child cases of severe sepsis per
1,000 habitants/year.11 Angus et al., across 847 federal hospitals
in the USA, in 1995, found three cases of severe sepsis for each group of 1,000
inhabitants and 2.26 cases for each group of 100 hospital discharges, 68% of
whom had received some sort of intensive or intermediate care. Global mortality
was around 28%, but varied according to age group: 10% of children and 38% elderly,
85 years or older.12 According to Brun-Buisson et al., based on French
adult ICUs, mortality at 28 days after discharge was 56% for severe sepsis and
60% for severe sepsis with a negative culture.13 In the study carried
out by Angus et al., the costs caused by sepsis were highest among infants,
non-survivors, patients in ICU, surgical patients and in those with failure
of more than one organ.12

The increase in
morbidity and mortality incidence rates related to sepsis of recent decades
is directly related to the medical advances achieved during this period, where,
more and more, seriously ill patients and those in more advanced stages are
treated. At least 50 of the cases reported on by Watson et al. Had a subjacent
disease, while 23% were low birth weight newborns.11 Another relevant
aspect which should be considered is that of secondary sepsis among critically
ill patients hospitalized for other reasons, whether because of immunological
compromise or because of medical conduct and procedures carried out during their
ICUs and hospital stay.14

The rates of sepsis
reported in published literature can vary according to local characteristics.
In the USA and Europe, sepsis is responsible for 2-11% of ICU admissions.15
A retrospective analysis by Jacobs et al., of more than 2000 Pediatric
ICU admissions, identified 42.5% of patients with and infectious disease, of
whom 63% had septic shock.16 Proulx et al., evaluating 1058 admissions
to a PICU at a Canadian teaching hospital, identified 82% Systemic Inflammatory
Response Syndrome (SIRS), of which 23% had infectious etiology (sepsis), 2%
of which had septic shock.9

Diagnosis

The diagnosis of
sepsis is the first of the challenges which confront the clinician or intensive
care specialist, especially because its identification, when not sufficiently
early to allow intervention, may result in shock, organ failure or even patient
death. Early sepsis diagnosis continues to be one of the most difficult of tasks,
whether because the first clinical manifestations may pass unnoticed or because
they can be confused with those of other, non infectious, processes. Furthermore,
the indirect laboratory indications (hemagram, coagulation study, glycemia,
etc), usually employed to reach a diagnosis of sepsis, individually have little
sensitivity and less specificity. Similarly, the results of bacteriological
examinations collected on the occasion of first suspicion are not immediately
available to guide specific therapy.

The criteria of
the 1991 Consensus which defined SIRS secondary to infection (sepsis), in addition
to being inappropriate for pediatric patients, were unspecific even for adult
patients. Observation and care of patients in Pediatric and Neonatal ICUs has
shown that the signs and symptoms of sepsis are highly variable, depending on
patient age group, and are not restricted to simply changes to certain physiological
variables. Thus, the younger the child, the less specific the symptoms of sepsis.
No clinical sign is sensitive or specific enough to indicate severe infection,
especially in seriously ill patients.14

A recent International
Conference on the Definition of Sepsis, while maintaining the definitions proposed
by the previous consensus, extended the list of possible clinical and laboratory
signs of sepsis, considering innumerable indicators of severe infection in the
child (Table 1). The researchers and experts considered
bedside diagnosis of sepsis to have priority over criteria for inclusion in
clinical studies.5

Therefore, for
the clinician or intensive care specialist, the diagnosis of sepsis is based
on a high level of suspicion, which demands a minutely detailed collection of
information on present status and medical history of the patient, a good clinical
evaluation, certain laboratory tests, in addition to rigorous clinical monitoring
of the patient. Faced with a suspicion of severe infection, the possibility
of other, non-infectious, systemic inflammatory conditions should be ruled out.

Laboratory

Laboratory, or
complementary, evaluation is capable of revealing two distinct aspects of sepsis.
The first is related to the search for the aggressive agent, by means of microbiological
tracking of the patient; the second relates to the identification of alterations
to metabolism or homeostasis, indicative of systemic compromise or of specific
organ involvement.

Microbiological
evaluation includes direct tests and cultures of blood (two or more), of urine,
of cerebrospinal fluid, of feces, of secretions, of small intestine aspirate,
of exudates, and of petechiae and suffusions (when meningococcemia is suspected),
preferably before using antimicrobial treatments (AMs). Cerebrospinal fluid
must always be obtained, especially for newborns and young infants, being careful
to obtain it safely, i.e. without risk to the patient.

In the case of
hospitalized patients, the collection of material for culture should include
all devices that breach the host's protective barriers, i.e. venous or arterial
catheters (blood from the catheters), vesicle probes, tracheal tube or tracheostoma
(tracheal aspirate), and stitches or scars from recent surgery.

Despite the great
effort made to isolate microorganisms, on average, blood cultures are positive
in 34% of "septic" patients, varying from 9 to 64%.18 How many of
these episodes are sepsis without bacteremia or failures of microbiological
cultivation and identification methods, or even non-infectious SIRS, remains
unknown.

On suspicion of
sepsis with a patient who has had a long duration ICU stay, an investigation
for systemic infection by fungus is mandatory. Currently, fungi, and especially
species of Candida, are responsible for around 5% of sepses.18 The
presence of additional risk factors increase the chance of fungal infection,
such as the use of multiple AM treatments, broad spectrum AMs, parenteral nutrition,
prolonged presence of central catheter and colonization of the digestive tract
by Candida.

The laboratory
evaluation to identify systemic compromise includes from the search for inflammatory
response indicators in peripheral blood (endogenous mediators, acute phase indicators)
to the testing for indicators of organic and metabolic disturbances in order
to treat and support them. Indicators of the presence of systemic inflammatory
response, in the majority, lack sensitivity and specificity for sepsis diagnosis,
but can be of value for prognosis and monitoring therapeutic response. Increases
in serum lactate, serum cytokines, granulocyte colony stimulating factor and
of plasma nitric oxide (by means of nitrite/nitrate plasma levels) can be early
indicators of SIRS, although the majority of them are not available quickly.
Procalcitonin, which is liberated into circulation together with cytokines,
and has a longer half-life, may have value for early diagnosis of neonatal sepsis.14
In adults, procalcitonin has been referred to as an indicator of sepsis
in patients with SRIS,19 and as a prognostic instrument with septic
patients.20 Despite its great potential, at the moment procalcitonin
cannot yet be defined as a marker for sepsis in patients with SIRS, and is perhaps
more useful for excluding the diagnosis.21

Treatment

The systemic inflammatory
response in sepsis, due to reasons that have not yet been established, may be
restricted to an self-limiting phenomenon or can proceed through stages of greater
severity, such as severe sepsis, septic shock and dysfunction or failure of
one or more organs. Despite the large number of investigations and reports on
SIRS, sepsis and related syndromes during recent years, and the undeniable improvement
in understanding their respective pathogeneses, the initial approach to sepsis
continues to be predominantly one of support. On suspicion of SIRS, if no other
significant, non-infectious event is detected, conduct should be directed at
sepsis; in addition to life support measures when indicated, other steps should
be taken depending upon the severity and presentation of the respective syndrome.

Early goal-directed
therapy

The limits separating
sepsis from severe sepsis, and this from septic shock or multiple organ failure
are not easily detected in clinical practice.8,9 During the course
of the evolution of the inflammatory response resuscitation phenomena such as
hypovolemia, peripheral vasodilation, myocardial depression, increased endothelial
permeability and hypermetabolism occur. Thus, in general, the intensive care
specialist is led to correct pre-load, post-load and cardiac contractility to
attend to the oxygen tissue supply/demand ratio, to maintain adequate cellular
perfusion and prevent organ dysfunction.22

Similarly, just
as the first hour is of extreme importance in the evaluation and primary care
of the trauma victim, with sepsis too, evolution to a more critical condition
in general occurs outside of the ICU. It is during the lapse of hours which
precedes the patient's admission to the ICU that early recognition of
poor evolution of sepsis and a more aggressive treatment can produce benefits
necessary to change the outcome.23

According to Rivers
et al.,24 early hemodynamic assessment with a basis in a physical
examination, on vital signs, on central venous pressure and urinary output is
not sufficient to detect persistent global tissue hypoxia. They recommend a
more definitive resuscitation strategy, with therapy oriented by goals, which
include manipulation of pre-load (CVP between 8 and 12 mmHg), post-load (MAP
>65 mmHg and <90 mmHg) and cardiac contractility (oxygen
saturation of mixed venous blood [SvO2] >70%),
to achieve equilibrium between supply and demand for systemic oxygen. The therapy
proposed, which should occur during the first 6 to 8 hours after identification
of the septic patient, including vigorous volumetric resuscitation every 30
minutes, until a CVP between 8 and 12 mmHg is achieved; use of vasopressors
if MAP <65 mmHg, attempting always to maintain it above this level, or use
of vasodilators if MAP >90 mmHg, attempting to maintain it below this
limit; and, if SvO2<70%, transfusion of erythrocyte concentrate
to achieve hematocrit at a minimum of 30%. After optimizing CVP, MAP and hematocrit,
if SvO2 remains <70%, use continuous dobutamine in increasing
doses until SvO2>70% or until dobutamine has reached a
limit of 20 µg/kg/min. The parameters for confirmation of the objective
proposed include the normalization of SvO2, arterial lactate concentration,
base cardiac output and pH. This strategy of early sepsis treatment directed
by objectives, when compared with a standard strategy resulted in fewer organic
dysfunctions and lower mortality.1,22,24

While there are
not yet any comparative studies available that use objective oriented therapy
with pediatric patients, some of the observations made by Rivers et al. probably
do not apply to children. In childhood septic shock there are always considerable
volume deficits, irrespective of invasive monitoring, the infusion of large
volumes of crystalloid solutions during the first hours of care is mandatory
and is associated with a reduced mortality rate.23 Even with a volumetric
deficit of 25 to 30% of the volemia, a child's MAP remains stable for a longer
period at the cost of increased systemic vascular resistance. In this manner,
MAP is not a good sign for indicating volumetric replacement in a child with
shock. Additionally, the use of dopamine is preferred for inotropic treatment
of children in place of dobutamine.23

Treatment
of the aggressive agent

Antimicrobial (AMs)
are the most specific and accessible agents for the treatment of patients with
infections, although they only represent a partial approach to the problem.
Over the last four decades, studies into the effects of AM use for severe infections
by gram-positive or gram-negative bacteria have demonstrated a considerable
reduction in the morbidity and mortality of populations affected by them.18
Antimicrobial can be of more use for the treatment of early clinical stages
of sepsis, before the host begins sequential mediator production resulting in
more advanced inflammatory cascade stages with severe tissue damage resulting.18
However, some authors have raised the idea that AMs may exacerbate the inflammatory
response due to destruction of the microorganisms, liberating material from
their cell walls and causing endogenous inflammatory mediators.2

Empirical AM treatments
have been recommended, in particular for patients with sever sepsis and septic
shock. Antimicrobial developed during the last decade, from the carbapenem group
(imipenem and meropenem), and third and fourth generation cephalosporins have
been proposed as monotherapy to replace aminoglycosides associated with a ß-lactamic
for severe sepsis and septic shock. Recommendations indicate the use of wide
spectrum penicillin AMs (associations with ticarcillin or piperacillin), of
monobactam (aztreonam) or of quinolones, in combined empirical therapies.18

The removal or
drainage of the infectious focus (e.g. peritonitis, empyema, septic osteoarthritis,
necrotized tissues), and equally the removal of infected foreign bodies (including
invasive devices), are important and relevant to stopping infectious stimuli,
since such measures would tend to reduce or end the production of endogenous
sepsis mediators, with a resultant reduction in the self-sustaining potential
of the systemic inflammatory response.

Treatment
aimed at improving innate immunity

One attempt to
improve the efficiency of antibiotics is to increase innate immunity, by increasing
the number of leukocytes. In a study by Rott et al., early use of filgrastim
with adult patients, despite achieving the effect expected from the drug (increasing
leukocytes to 75 x 109 cells/l), did not change patient 28-day mortality.25

Therapy aimed
at the systemic inflammatory response

The majority of
researchers agree that improved severe sepsis survival rates can only be achieved
with additional therapies as well as conventional antimicrobial treatments.
The more the complexity and interdependence of the pathophysiological mechanisms
of sepsis are understood, the more therapeutic strategies based on substances
which modulate or interrupt the effects of endogenous and exogenous sepsis mediators
are sought.

The therapeutic
strategy which appears to have the greatest chance of changing the disheartening
results of sepsis treatment is to intervene at any point in sequence of pathophysiological
events which characterize the systemic inflammatory response in sepsis, in order
to modify (modulate) the host's reaction. Unfortunately, the clinical
use of treatments which block individual mediators has failed to reduce the
general mortality associated with sepsis (Table
2).

Agents which bond
with or neutralize components in the bacterial cell wall (anti-endotoxin antibodies,
lipopolysaccharide binding protein antagonist, CD14 receptor inhibitor, permeability-increasing
protein antagonist) or those which modulate the immediate response of the host
to these toxic products (pentoxifylline, amrinone) did not prove to be valid
for sepsis treatment. The majority of studies realized to date did not reveal
definitively negative results, but answers continue to be sought by means of
better designed collaborative studies. A double-blind, randomized and controlled
multicenter study of 847 patients at 53 hospitals in the USA, using two doses
of monoclonal E5 antibody against endotoxin, demonstrated that there was no
reduction in mortality among patients with sepsis from gram-negative germs with
no shock, but that there was greater recovery from organ failure among these
patients.27 A more recent study, which used the human monoclonal
antibody to a common enterobacteria antigen, also failed to reduce mortality.28

Pentoxifylline,
in common with amrinone, inhibits phosphodiesterase, increasing concentrations
of intracellular cyclic AMP, resulting in a reduction in cytokine accumulation,
especially TNF- a. A European double-blind and randomized
study of 100 newborns, demonstrated reduced mortality among premature sepsis
patients within the group that received pentoxifylline, 5 mg/kg/h for 6 hours,
on 6 consecutive days.29

Although, in theory,
corticosteroids have always been considered to have some sort of cytokine synthesis
blocking action, their use and efficacy for sepsis or septic shock have not
been supported by clinical evidence and there are even studies that suggest
their use may be prejudicial to these patients.30 More recently,
interest has once more increased in using corticosteroids for sepsis. The observation
that severe sepsis may be associated with relative adrenal insufficiency or
resistance to glucocorticoid receptors induced by systemic inflammation has
awoken interest in studies which evaluate the usefulness of low dose corticoids
in sepsis situations. A randomized, double-blind, placebo-controlled study carried
out by Annane et al., indicated that extremely ill patients with sepsis and
persistent shock, requiring vasopressors and mechanical ventilation, benefited
from the use of physiological doses of corticosteroids for 7 days, with reductions
in duration of com vasopressor use and mortality rate when compared with the
controls.31 Similarly, a recent randomized, double-blind, placebo-controlled
study by Keh et al., indicated that continuous, low dose, hydrocortisone use
was of benefit to patients in septic shock, restoring hemodynamic stability
when compared with controls.32

Agents which neutralize
or prevent the action of inflammatory cytokines on their respective receptors,
such as monoclonal anti-TNF-a antibodies tend to
reduce the production of the next mediators in the inflammatory cascade (interleukin-1
[IL-1] and interleukin-6 [IL-6]), would hypothetically prevent
pathophysiological damage, improving survival rates. A randomized, double-blind
and controlled multicenter study of 1,879 patients at 105 hospitals in the USA
and Canada, using murine monoclonal antibodies for TNF-a
(TNF-a Mab), did not reveal differences in 28-day
mortality between patients who had received the antibody and those who had received
placebos.33 Another randomized, double-blind and controlled multicenter
study of 498 patients at 44 hospitals in the USA and Europe, receiving soluble
TNF-a receptor fusion protein (p55), also failed
to reveal reduced mortality among those who received the antibody in comparison
with those who received the placebo.34

Interleukin-1 receptor
antagonist tend to attenuate hemodynamic alterations, reducing the severity
of lactic acidosis and improving survival rates. The Interleukin-1 Receptor
Antagonist Sepsis Investigator Group, by means of a randomized, double-blind
and controlled multicenter study of 696 patients at 91 hospitals in the USA
and Europe, did not demonstrate reduced mortality with the use of human recombinant
IL-1 receptor antagonist when compared with a placebo.35

Platelet activation
factor, PAF, is a phospholipid produced by macrophages, neutrophils, platelets
and endothelial cells, which can mediate the effects of innumerable cytokines.
Thus, PAF receptor antagonists may be useful for treating sepsis due to gram-negative.
A randomized, double-blind and controlled multicenter study of 600 patients
with severe sepsis which tested PAF receptor antagonist for four days, did not
demonstrate any reduction in mortality rate.36

It is now known
that nitric oxide production, (NO endogenous vasodilator), is responsible for
some of the harmful effects of the inflammatory response on target organs (vasodilation
and hypotension; myocardial depression in septic shock). It is produced from
L-arginine with the aid of NO synthase (NOs) and its inhibition or blockage
is a therapeutic strategy to minimize these effects. Although its inhibition
in animals with sepsis can lead to arterial pressure normalization, may result
in other undesirable effects (e.g. reduced cardiac index and increased pulmonary
pressure). It is thought that inhibiting NOs - L-NAME (N-nitro-L-arginine methyl
ester) would also inhibit the beneficial effects of NO, and that only in situations
of NO overproduction could this agent have any real benefit. The strategy of
employing NOs inhibitors has not been sufficiently tested on humans.

The process of
PMN activation and degranulation caused by inflammatory mediators results in
large scale free radical production. It is believed that endogenous antioxidants
(vitamins C and E, ß-carotene, catalase and superoxide dismutase) would
not be sufficient to neutralize this exposure to free radicals and avoid cellular
damage in SIRS. Studies of sepsis in animal models have shown beneficial effects
from treatment with substances to scavenge oxygen free radicals (superoxide
dismutase and catalase).2,24 Other treatments with antioxidant agents
(a-tocopherol, dimethyl sulphoxide, Q10 coenzyme, N-acetylcysteine, glutation,
allopurinol, among others) are being evaluated in animal tests; results are
so far inconclusive.

It is believed
that products of the metabolism of arachidonic acid, by both routes (cyclooxygenase
and lipooxygenase), and also prostaglandins and thromboxanes appear to perform
a considerable role in target organs when the inflammatory response evolves
and there is organ dysfunction. A number of different cyclooxygenase inhibitors
(indomethacin, ibuprofen) appear to have beneficial effects at specific points
in the inflammatory cascade and on the survival of animals. A randomized, double-blind
and controlled multicenter study of ibuprofen with 455 sepsis patients revealed
reduced prostacyclin and thromboxane levels, reductions in fever, tachycardia,
lactic acidosis and oxygen consumption, but without preventing the development
of shock or respiratory distress syndrome or improving patient survival.37
A study by Arons et al. of patients with hypothermal sepsis, compared with febrile
patients, demonstrated reduced mortality among patients treated with ibuprofen.38
The majority of therapeutic strategies with non-steroidal antiinflammatories,
both those attempted to date and those which are still under investigation have
failed to produce definitively positive results for treatment of severe sepsis
and septic shock. A meta-analysis of 18 clinical trials at phases II and III
on the use of non-steroidal agents with antiinflammatory properties for sepsis
treatment, based on 6,429 patients, demonstrated that there were only beneficial
tendencies without significantly altering mortality.3

Heparin has also
been studied for sepsis treatment, for its immunomodulatory properties and because,
in vitro it inhibits the bond between L- and P-selectin, based on the
observation that rats that are deficient in L-selectin are immune to lethal
endotoxemia. In a randomized, double-blind, placebo-controlled study, Derhaschnig
et al. tested non-fractioned heparin and low molecular mass heparin, after lipopolysaccharide
infusion on healthy volunteers The group that received non-fractioned heparin,
there were significant reductions in lymphocytopenia and in L-selectin down-regulation
induced by the toxin, providing evidence that heparin has a probable mechanism
of action of use in the treatment of sepsis.39

Another anticoagulant
which has been investigated for sepsis treatment is antithrombin, which combines
two effects: in addition to being an anticoagulant it also has antiinflammatory
effects, inhibiting proteases which interact with cells that liberate proinflammatory
mediators. The bond with syndecan-4 receptors interferes with intracellular
signals induced by mediators such as lipopolysaccharide. It has been described
as being of benefit in small cohorts of septic patients with coagulation disorders.40
However in a large phase III multicenter, double-blind, placebo-controlled trial
(KyberSept Trial), involving 2,314 adults with severe sepsis, the use of antithrombin
III started within the first 6 hours did not reduce 28-day mortality (primary
objective) or at 56 and 90 days (secondary objective). When the sample was stratified
for concurrent heparin and antithrombin use, there was no difference in 28-day
mortality, but 90-day mortality was significantly less for the group that did
not receive heparin.41 Concurrent heparin use, in addition to producing
m ore hemorrhages, may have reduced the antiinflammatory effect of antithrombin.
Later, Hoffmann et al. demonstrated that, in a laboratory, the of use antithrombin
prevented, to a significant extent, endothelium-leukocyte interaction and capillary
damage, in animal sepsis models from lipopolysaccharide injection; however,
among the animals that received antithrombin associated with heparin, lesions
were similar to those that occurred in the controls (that had only received
the toxin), thus demonstrating the adverse effects of associating the two drugs.42
A multicenter, observational study, carried out in Italy with 216 patients who
received antithrombin for sepsis, CIVD and other clinical conditions also concluded
that this therapy did not benefit the sepsis patients in terms of mortality.
In this sample there was no difference linked to concurrent heparin use.43

It has been observed
that many critical patients, even those who are not diabetic, have hyperglycemia
and a reduced response to endogenous insulin, possibly because of increases
in the levels of insulin-like growth factor binding protein. The use of exogenous
insulin to maintain glycemia within normal parameters has proved to be of benefit,
in terms of outcome, with patients suffering from myocardial infarction . There
is a hypothesis that in sepsis, normoglycemia restores neutrophil phagocytic
capacity, compromised by hyperglycemia. Another potential mechanisms is the
antiapoptotic effect of insulin from activation of the phosphatidylinositol
3-kinase-Akt pathway.1,22 Based on these principles, a randomized,
controlled, prospective study was conducted of 1,548 adult patients post heart
surgery, on mechanical ventilation. The control group received insulin infusion,
when necessary to maintain glycemia between 180 and 220 mg/dl, while the treatment
group received systematic insulin in order to maintain normoglycemia (glucose
between 80 and 110 mg/dl). The treatment group had reduced 5-day mortality by
32% (primary objective) and also lower mortality during hospitalization, lower
multiple organ failure mortality and fewer sepsis episodes (secondary objectives).47

Another strategy
which has been suggested and has already won a place among sepsis treatment
strategies use the techniques of extracorporeal substitution, such as continuous
arterio-venous hemofiltration and plasmapheresis, especially in cases of severe
sepsis and MOFS. They may be used at any phase of the inflammatory process with
the objective of reducing concentrations of inflammatory cascade inflammatory
mediators (exogenous and endogenous), and consequentially their potential to
cause damage to target organs. A multicenter, randomized and controlled, multicenter
clinical trial at seven tertiary ICUs with 30 patients with sepsis subjected
to continuous plasmapheresis for 34 hours, only found attenuation of the acute
phase sepsis response and a reduced tendency to organ failure, but with no effect
of cytokine response or on final mortality.48 A randomized and controlled
clinical trial involving 106 adult patients with severe sepsis or septic shock,
showed that the group treated with plasmapheresis had a mortality rate 28 days
after discharge that was 20% lower than the control group that received standard
treatment for shock.49

Despite some initially
encouraging results, the majority of research into substances that are inflammatory
reaction modulators failed to effectively reduce mortality. The reasons postulated
for this failure include disparities between animal models and clinical reality,
the heterogeneous nature of the patients and their manifestations of sepsis,
and the complexity of the inflammatory cascade.50

Other potential
therapies

Innumerable new
agents appear to be effective in animal models, creating new hope for sepsis
treatment. Interferon-g has been considered capable
of restoring macrophage HLA-DR expression and TNF-a
production in patients with sepsis. The administration of antibodies against
products of C5a activation reduced the frequency of bacteremia, preventing apoptosis
and improving survival. The administration of antibodies against macrophage
migration inhibitory factor protected rats from peritonitis. Strategies to block
lymphocyte or gastrointestinal epithelial cell apoptosis have improved survival
rates in experimental sepsis models.1

Concluding, we
can state that, despite the diagnostic technological advances of recent years,
little progress has been achieved in terms of changing the mortality of sepsis.
This is due to the complexity of aggressor-host relationships, which cannot
be regulated and whose modulation depends much more on host response than on
therapeutic intervention. Certain strategies are certainly of benefit, such
as early recognition of sepsis, aggressive initial intervention against hemodynamic
disturbances and rational handling of antimicrobial. Any advance in the understanding
of the these three strategies will undoubtedly increase the chances of a good
prognosis, although it is not expected that the increase would be of any great
magnitude. The combination of immunomodulatory therapies appears to be the future
for research in this area. Corticoid use, for patients with or without adrenal
insufficiency is resurfacing as a promising strategy. Similarly, drotrecogin-a
appears to be the only substance which has demonstrated an impact on mortality,
although in an unexceptional manner. Nevertheless, we recommend caution with
the initial enthusiasm about drotrecogin, taking into account the fact that
since the publication of the original experiment there has been no reproduction
of the research in a different scenario. Because of the peculiarities of children,
the scarcity of studies and the complexity of sepsis in this age group, pediatricians
should be alert to new discoveries in this area.

4. American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference: Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Crit Care Med 1992;20:864-74. [ Links ]

6. American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference: Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Crit Care Med 1992;20:864-74. [ Links ]